1. Field of the Invention
The invention is directed to the in situ precoating and preopsonization by direct application of a full repertoire of immunoglobulins (IgG, IgA, IgM, and parts thereof) to the surfaces of tissues and biomaterials for the prevention and treatment of microbial adhesion, colonization, and infection in man and animals.
2. Description of the Prior Art
Surgical wound infection, especially biomaterial centered, or sepsis subsequent to major trauma with bacterial contamination, continues to be a significant problem in morbidity and cost even with the use of antibiotics. There are twenty five million surgeries each year in the United States and an equivalent number in Europe. Although rates of infection are quite low for most elective surgeries, they are significantly higher in the presence of biomaterial implants or traumatized tissue and range from less than 1% for total hips, to 6% for vascular grafts, half of which culminate in amputation or death. The rate of infection for the total artificial heart is essentially 100% if awaiting bridge to transplant for more than ninety days. Most often, and interestingly, infections about biomaterials cannot be cured without removal of the implant, even with massive doses of antibiotics. Major contaminated wounds and open fractures such as occur in industry, auto trauma, and warfare also have up to and more than a 10% rate of sepsis. Biomaterial centered infection is discussed in Gristina, Science, 237:1588-1595 (1987), Gristina et al., JAMA, 259:870-874 (1988), and Gristina et al., "Molecular Mechanisms in Musculoskeletal Sepsis: The Race for the Surface", Chapter 58 of Instructional Course Lectures, Vol. XXXIX 1990, ed. Greene, American Academy of Orthopaedic Surgeons.
All burns are colonized by bacteria. Large 2.degree. and 3.degree. burns produce severe local and systemic sepsis, toxin release, additional tissue destruction, and bacteremia.
Streptococcal infections, endocarditis, and pneumonia also persist as serious problems for at risk groups. Tuberculosis and secondary opportunistic pathogens are among the recurring diseases in immuno compromised patients (AIDs). For these diseases, antibiotics are often ineffective, not timely or deliverable. Respiratory, genitourinary, and gynecologic mucosal surfaces are vulnerable to recurrent and chronic bacterial and viral invasion.
The two important causal mechanisms for these infections are: (1) microbial adhesion to damaged tissue or biomaterial substrata and the formation of bacterial biofilms which shield microorganisms from host defenses and antibiotics, and (2) disruption of host defenses and the production of an immunoincompetent inflammatory zone at damaged tissues and biomaterial interfaces. Biomaterial surfaces, their particulate debris, severe tissue trauma, and burns cause massive and chronic inflammatory responses characterized by host defense mechanism exhaustion. Additionally 1.degree. and 2.degree. immuno deficiency states (e.g., AIDs, the aged, diabetics, etc.) cause increased host susceptability to pathogens.
Currently antibiotics are the treatment of choice for most bacterial diseases, but they tend to be ineffective against contaminated open fracture, biomaterial centered, foreign body and burn infections, cannot be extensively used to preempt infection, and do not potentiate host defenses. Antibiotics and host defenses (immunoglobulins) usually are ineffective after bacteria have formed protective biofilms (see, Gristina, Science, 237:1588-1595 (1987), Gristina et al., JAMA, 259:870-874 (1988), and Gristina et al., "Molecular Mechanisms in Musculoskeletal Sepsis: The Race for the Surface", Chapter 58 of Instructional Course Lectures, Vol. XXXIX 1990, ed. Greene, American Academy of Orthopaedic Surgeons). Furthermore, use of antibiotics causes selection for the survival of drug-resistant strains.
Higher animals have, by evolution, established several very effective means of defense against microbes involving the immune system. Invading bacteria are rapidly identified, via complement and immunoglobulin opsonization, phagocytized and destroyed by the cellular immune system and white blood cells (neutraphils and macrophages). Globulins are essentially nature's perfect antibodies. Complement, available as a precursor protein which is activated by the presence of microorganisms and globulins, also functions in antibacterial activities. Opsonization of foreign organisms is the memory component of the immune system. After previous antigenic exposure, the immune system produces a series of globulins which attach to and coat bacteria or neutralize viruses so that they are readily recognized, phagocytosed and destroyed by neutrophils and macrophages. Foreign proteins of invading organisms also stimulate a humoral immune response which over a period of time (3-6 weeks) amplifies the numbers of cells designed to recognize and destroy specific invaders. Tables 1 and 2 present the antimicrobial functions of immunoglobulins and the metabolic properties of immunoglobulins.